Regulation of glucose tolerance in patients after liver transplantation: impact of cyclosporin versus tacrolimus therapy

Background. We investigated the factors regulating glucose homeostasis in 10 healthy (control) subjects, as well as in stable, long-term, liver-grafted patients receiving monotherapy in the form of either cyclosporin A (n=10) or tacrolimus (n=10). Methods. We measured insulin sensitivity, first- and second-phase insulin secretion, with a minimal modeling technique based on the analysis of glucose, insulin, and C-peptide profiles during frequently sampled intravenous glucose tolerance tests (FSIGTT). Proinsulin levels, as a marker of β-cell dysfunction, were measured in the fasting state and during FSIGTT. Results. Glucose and insulin concentrations before and after glucose loading did not differ in liver transplant patients and in control subjects. Fasting C-peptide levels in both liver-grafted groups were higher than in healthy subjects and remained elevated during FSIGTT (P <0.05). Intravenous glucose tolerance [(KG), i.e. the slope of the regression of logarithm of the blood glucose concentrations vs. time], insulin sensitivity, and first-phase insulin secretion did not differ in liver-grafted groups and healthy subjects. Second-phase insulin secretion was about 56% higher in liver-grafted patients than in controls (P <0.05). Body mass index was the overall determinant of insulin sensitivity in all groups. Conclusions. Long-term monotherapy with cyclosporin A or tacrolimus has no deleterious effects on insulin sensitivity, first-phase insulin secretion, and insulin synthesis in liver transplant patients. Normal insulin sensitivity (posthepatic insulin effect) and enhanced second-phase insulin secretion (prehepatic insulin) point to an accelerated hepatic insulin clearance rate in liver transplant patients. Increased hepatic insulin clearance is compensated by enhanced insulin secretion, indicating that insulin clearance is the major determinant of pancreatic function in liver-grafted patients.